In diseases such as osteoarthritis and rheumatism, the joint is destroyed, with this destruction being due, in particular, to the proteolytic breakdown of collagen by collagenases. Collagenases belong to the superfamily of the metalloproteinases (MPs) or matrix metalloproteinases (MMPs). The MMPs form a group of Zn-dependent enzymes which are involved in the biological breakdown of the extracellular matrix (D. Yip et al. in Investigational New Drugs 17 (1999), 387-399 and Michaelides et al. in Current Pharmaceutical Design 5 (1999) 787-819). These MMPs are able, in particular, to break down fibrillar and nonfibrillar collagen and proteoglycans, both of which are important matrix constituents. MMPs are involved in processes of wound healing, tumor invasion, metastasis migration and in angiogenesis, multiple sclerosis and heart failure (Michaelides page 788; see above). In particular, they play an important role in the breakdown of the joint matrix in arthrosis and arthritis, whether it is osteoarthrosis, osteoarthritis or rheumatoid arthritis.
The activity of the MMPs is furthermore essential for many of the processes which play a role in the formation of atherosclerotic plaques, such as the infiltration of inflammatory cells, the migration of smooth muscle cells, and proliferation and angiogenesis (S. J. George, Exp. Opin. Invest. Drugs (2000), 9 (5), 993-1007). In addition, degradation of the matrix by MMPs can cause anything from plaque instabilities through to ruptures, with this being able to lead to the clinical symptoms of atherosclerosis, unstable angina pectoris, myocardial infarction or stroke (E. J. M. Creemers et al., Circulation Res. 89, 201-210 (2001)). All in all, the complete MMP family is able to break down all the components of the blood vessel extracellular matrix; for this reason, their activity is to a high degree subject to regulatory mechanisms in normal blood vessels. The increase in MMP activity during plaque formation and plaque instability is caused by an increase in cytokine-stimulated and growth factor-stimulated gene transcription, an increase in zymogen activation and an imbalance in the MMP/TIMP (tissue inhibitors of metalloproteases) ratio. It therefore seems plausible that MMP inhibition or the reattainment of the MMP/TIMP equilibrium would be of assistance in treating the atherosclerotic diseases. It is also becoming ever clearer that aside from atherosclerosis, an increase in MMP activity is also at least a contributory cause of other cardiovascular diseases such as restenosis, dilated cardiomyopathy and the already mentioned myocardial infarction. It has been shown that administering synthetic inhibitors in experimental animal models can achieve marked improvements in these diseases as regards, for example, formation of atherosclerotic lesions, neointima formation, left-ventricular remodeling, pumping output malfunction or infarction healing. In a variety of preclinical studies using MMP inhibitors, detailed tissue analysis indicated a reduction in collagen damage, an improvement in extracellular matrix remodeling and an improvement in the structure and function of cardiac muscle and blood vessels. Of these processes, matrix remodeling processes and MMP-regulated fibroses are regarded, in particular, as being important components in the progress of cardiac diseases (infarction) (Drugs 61, 1239-1252 (2001)).
MMPs cleave matrix proteins, such as collagen, laminin, proteoglycans, elastin or gelatin, and also process (i.e., activate or deactivate), by means of a cleavage, a large number of other proteins and enzymes under physiological conditions, which means that they play an important role in the entire organism, with this role being of particular importance in connective tissue and bone.
A large number of different inhibitors of the MMPs are known (EP0606046; WO94/28889; WO 96/27583; or also overviews such as Current Medicinal Chemistry 8, 425-74 (2001)). Following the first clinical studies in humans, it has now been found that MMPs give rise to side effects. The side effects that are principally mentioned are musculoskeletal pains or anthralgias. The prior art states unambiguously that it is expected that more selective inhibitors will be able to reduce these said side effects (Yip, page 387, see above). Particular emphasis should be placed in this case on specificity in respect to MMP-1, as these undesirable side effects obviously occur to a greater extent with inhibition of MMP-1.
The known MMP inhibitors therefore frequently suffer from the disadvantage of lacking specificity. Most MMP inhibitors inhibit many MMPs simultaneously because the structure of the catalytic domain in the MMPs is similar. As a consequence, the inhibitors have the undesirable property of acting on the enzymes including those that have a vital function (Massova, I., et al., The FASEB Journal (1998) 12, 1075-1095).
In view of the current situation, it is clear that there is a need for a compound that is a powerful inhibitor of the matrix metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 whereas it has only a weak inhibitory effect on MMP-1.